title: Activation of α2 adrenoceptors inhibited NMDA receptor-mediated nociceptive transmission in spinal dorsal horn of mice with inflammatory pain.
abstract: The α2 adrenoceptor is highly enriched in spinal dorsal horn and involved in descending noradrenergic pain modification. Following peripheral tissue injury, intrathecal application of α2 adrenoceptor agonists effectively alleviates the pathological pain hypersensitivity, although the precise mechanisms are not fully understood. The present study induced inflammatory pain by intraplantar injection of Complete Freund's Adjuvant (CFA), and prepared the spinal cord slices to assay the possible influence of α2 adrenoceptor agonist clonidine on the synaptic transmission mediated by NMDA receptor (NMDAR), a critical player in spinal sensitization. Whole-cell patch clamp recordings in lamina II neurons illustrated that clonidine significantly decreased the amplitudes of NMDAR-mediated monosynaptic responses in inflamed mice through activation of α2A-subtype adrenoceptor. No significant alteration in the paired-pulse ratio before and after clonidine application indicated the postsynaptic origin. Intracellular loading of nonhydrolyzable GDP analog GDP-β-S blocked, whereas direct inhibition of cAMP-dependent protein kinase (PKA) mimicked, the inhibitory effect of clonidine on NMDAR currents, implicating that Gαi protein/PKA signaling was involved in clonidine action. Biochemical analysis in vivo revealed that intrathecal clonidine administration specifically decreased the content of GluN2B subunit-containing NMDAR at synaptosomal membrane fraction, a result associated closely with the alleviation of inflammatory pain. Electrophysiological recordings in vitro further demonstrated that GluN2B receptor-selective inhibitor ifenprodil dramatically reduced NMDAR synaptic responses in inflamed mice and more importantly, occluded the synaptic inhibition produced by clonidine. These data suggested that the noradrenergic suppression of inflammatory pain might involve the blockade of GluN2B receptor-mediated nociceptive transmission in spinal dorsal horn.
authors.affiliation: Department of Molecular Pharmacology, School of Pharmacy, Lanzhou University, Lanzhou, Gansu 730000, PR China.
authors.forename: Qing-Qing
authors.initials: QQ
authors.lastname: Fan
authors.affiliation: Department of Molecular Pharmacology, School of Pharmacy, Lanzhou University, Lanzhou, Gansu 730000, PR China.
authors.forename: Lu
authors.initials: L
authors.lastname: Li
authors.affiliation: Department of Molecular Pharmacology, School of Pharmacy, Lanzhou University, Lanzhou, Gansu 730000, PR China.
authors.forename: Wen-Tao
authors.initials: WT
authors.lastname: Wang
authors.affiliation: Department of Molecular Pharmacology, School of Pharmacy, Lanzhou University, Lanzhou, Gansu 730000, PR China.
authors.forename: Xian
authors.initials: X
authors.lastname: Yang
authors.affiliation: Department of Molecular Pharmacology, School of Pharmacy, Lanzhou University, Lanzhou, Gansu 730000, PR China.
authors.forename: Zhan-Wei
authors.initials: ZW
authors.lastname: Suo
authors.affiliation: Department of Molecular Pharmacology, School of Pharmacy, Lanzhou University, Lanzhou, Gansu 730000, PR China. Electronic address: huxxiaodong@lzu.edu.cn.
authors.forename: Xiao-Dong
authors.initials: XD
authors.lastname: Hu
mesh_terms: D058647:Adrenergic alpha-2 Receptor Agonists / Q000494:pharmacology*; D000818:Animals; D003000:Clonidine / Q000494:pharmacology; D007249:Inflammation / Q000378:metabolism* / Q000503:physiopathology; D008297:Male; D051379:Mice; D059225:Nociception / Q000187:drug effects / Q000502:physiology*; D010146:Pain / Q000378:metabolism* / Q000503:physiopathology; D020671:Posterior Horn Cells / Q000187:drug effects / Q000378:metabolism*; D018341:Receptors, Adrenergic, alpha-2 / Q000378:metabolism; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism*; D013116:Spinal Cord / Q000187:drug effects / Q000378:metabolism* / Q000503:physiopathology; D009435:Synaptic Transmission / Q000187:drug effects / Q000502:physiology
chemical_list: D058647:Adrenergic alpha-2 Receptor Agonists; C121001:NR2B NMDA receptor; D018341:Receptors, Adrenergic, alpha-2; D016194:Receptors, N-Methyl-D-Aspartate; D003000:Clonidine
keywords: Inflammatory pain; NMDA receptor; Spinal dorsal horn; Synaptic transmission; α2 adrenoceptor